Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade

被引：205

作者：

Bonavita, Eduardo ^{[1
]}

Bromley, Christian P. ^{[1
]}

Jonsson, Gustav ^{[2
]}

Pelly, Victoria S. ^{[1
]}

Sahoo, Sudhakar ^{[1
]}

Walwyn-Brown, Katherine ^{[3
]}

Mensurado, Sofia ^{[4
]}

Moeini, Agrin ^{[1
]}

Flanagan, Eimear ^{[1
]}

Bell, Charlotte R. ^{[1
]}

Chiang, Shih-Chieh ^{[1
]}

Chikkanna-Gowda, C. P. ^{[1
]}

Rogers, Neil ^{[5
]}

Silva-Santos, Bruno ^{[4
]}

Jaillon, Sebastien ^{[6
]}

Mantovani, Alberto ^{[6
]}

Sousa, Caetano Reis E. ^{[5
]}

Guerra, Nadia ^{[2
]}

Davis, Daniel M. ^{[3
]}

Zelenay, Santiago ^{[1
]}

机构：

[1] Univ Manchester, Canc Res UK Manchester Inst, Alderley Pk, Manchester, Lancs, England

[2] Imperial Coll London, Dept Life Sci, London, England

[3] Univ Manchester, Manchester Collaborat Ctr Inflammat Res, Lydia Becker Inst Immunol & Inflammat, Manchester, Lancs, England

[4] Univ Lisbon, Fac Med, Inst Med Mol Joao Lobo Antunes, Lisbon, Portugal

[5] Francis Crick Inst, London, England

[6] Humanitas Univ, IRCCS, Humanitas Clin & Res Ctr, Dept Biomed Sci, Milan, Italy

来源：

IMMUNITY | 2020年 / 53卷 / 06期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

NATURAL-KILLER-CELLS; CLINICAL-RESPONSE; CTLA-4; BLOCKADE; DENDRITIC CELLS; PD-1; CANCER; LANDSCAPE; SENSITIVITY; CONTEXTURE; BIOMARKERS;

D O I：

10.1016/j.immuni.2020.10.020

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-gamma)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.

引用

页码：1215 / +

页数：23

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